10-[2&#39;-(n-alkyl-piperidyl-2&#39;&#39;)-ethyl-1&#39;]-phenothiazines containing a substituent in 3-position



United States Patent 1 cc -[2'- (N -ALKYL-PIPERIDYL-2" -ETHY L-l'] -PHENO- THIAZINES CONTAINING A SUBSTITUENT IN S-POSITION Arthur Stoll, Arlesheim, Baselland, and Jany Renz and Jean-Pierre Bourquin, Basel, Switzerland, assignors to Sandoz Ltd., Basel, Switzerland No Drawing. Application January 14, 1958 Serial No. 708,773

Claims priority, application Switzerland July 23, 1954 8 Claims. (Cl. 260-243) The present invention is concerned with therapeutically useful phenothiazines which contain an N-alkyl-piperidyl- 2-ethyl group at the phenothiazine nitrogen atom and also contain a substituent in the 3-position of the phenothiazine nucleus.

The phenothiazines according to the present invention thus correspond to the formula (I311: (I) wherein R may be a halogen atom or an alkoxy group (1 to 4 carbon atoms).

The compounds of Formula I may be prepared, according to this invention, by condensing a phenothiazine derivative which corresponds to the formula to the nitrogen atom with a B-halogenoethyl group, said amine corresponding to the formula Cg: $a C Halogen-CHrCHr-CH CH;

wherein halogen is a chlorine or bromine atom.

The condensation may, for example, be carried out as follows:

A phenothiazine derivative of Formula II is dissolved in an organic solvent, such for example as benzene, toluene, xylene, etc., and is then heated together with a ,B-halogenoethyl derivative of Formula III in the presence of an alkaline condensing agent such for example as an alkali metal or an alkali metal compound such as the hydroxide, amide, hydride or alkanolate. The reaction may also be carried out at ordinary temperature (e.g. at about 2030 C.). It is also possible to carry out the reaction without employing a solvent, i.e. in the phenothiazine melt, in which case a condensing agent may also be omitted, although in some cases the yield may be somewhat reduced. Upon completion of the reaction, the reaction, mixture is (III) 2,902,486 Patented Sept. 1, 1959 shaken out with water, and is then freed of solvent under reduced pressure. The new compounds may, however, also be extracted from the reaction mixture by means of dilute mineral or organic acid and then precipitated from the aqueous phase by the addition of caustic alkali or ammonia. The obtained new bases can be filtered off in those cases where they separate out in solid form, or where they separate out in oily state, can be taken up in benzene or another water-immiscible solvent and then again freed of solvent by evaporation. The bases can be purified by distillation in a high vacuum and/or by conversion into salt form. i

The compounds of this application are primarily useful as specific sedatives, i.e. tranquillizers, and thus are useful in the treatment of states of excitement and anxiety due to various psychoses, states of illusion and delusion, and states of tension and unrest of any source, e.g. in connection with arteriosclerosis, neurosis in climacterium, in connection with vegetative disturbances, insomnia, various forms of vomiting, e.g. in pregnancy, and in the reduction of pain.

Useful and reliable pharmacological tests have to be based on their specific action in animals and their characteristic mechanism of action: According to present knowledge, this concerns (a) the central and peripheral adrenolytic activity, and (b) the sedative action per se which can reliably be tested by the potentiating activity of hypnotic drugs.

(ad a) The antagonism of the phenothiazine derivatives to epinephrine takes place at peripheral and central sites and especially also at the formation reticulauris in the midbrain, a substrate which is specifically influenced by 3-chloro-l0-(dimethylamino-propyl-3')-phenothiazine and other effective phenothiazine derivatives. The adrenolytic potency of these compoundswhich the art considers as an essential action of psychosedatives-has thus been used repeatedly to test tranquillizers of the phenothiazine type.

(ad b) Courvoisier et a1. (1948) first found that 3- chloro 10 (dimethylamino propyl 3') phenothiazine (Chloropromazine) potentiates the hypnotic efiect of barbiturates. This property of these drugs is essential for their clinical tranquillizing effect, since all clinically effective phenothiazine derivatives potentiate hypnosis.

The compounds of the present application were screened for their adrenolytic potency and their potentiating elfect on barbiturate hypnosis. The following methodswere employed for this comparison:

(i) Adrenolytic efiect.The inhibitory elfect of these substances on epinephrine-induced contractions of the isolated seminal vesicle of the guinea pig was analyzed. The inhibitory potency was in each instance compared with that of a standard drug, dihydroergotamine (DHE), which is a highly potent adrenergic blocking agent. Its potency was expressed as being of the strength 1; the potency of a drug 3 times as strong as DHE, for example, is therefore expressed by 3. (Literature on DHE and methods: Rothlin et al., Helv. Physiol. Acta 3, C 43, 1945.)

(ii) Potentintion of narc0sis.-For the assay of bar biturate potentiation, the method described by M. Taeschler and A. Cerletti in J. Pharmacol. Exp. Therap. 120, 179 (1957) was employed. The test was performed on mice of a uniform strain. The substances to be tested were injected 10 minutes before the narcotic barbiturate. The barbiturate potentiating activity is expressed by the percentage of mice which show a narcosis for more than 2 minutes following injection of a non-narcotic dose of Pentothal (20 mgs. per kg. body weight intravenously). ED for example, is the dose to which 50 percent of the total number of mice respond by a narcosis of more than 2 minutes.

and especially Compound II, are so weal; in their action as to render them practically useless in therapy.

Moreover, in compounds of the type here involved, the substitution by a halogen atom or by an alkoxy group in the 3-position results in much stronger activities than does substitution by an alkyl or an hydroxy group. Likewise the 3-unsubstituted compounds are only weakly active and of no practical utility since the therapeutic doses thereof lie in the toxic range.

In the following table, the comparative action of S-halogenoor 3-alkoxy-10-I2'-(N-methyl-piperidyl-2")- ethyl-lJ-phenothiazine with such phenothiazine derivatives is demonstrated. it

IV: 3-methoxy [2 -(N-methyl-piperidyl-2")-ethyl- 1]-phenothiazine V: 3-isopropoxy 10 [2'-(N-methyl-piperidyl-2")-ethyl- 1' -phenothiazine VI: 10 [2-(N-methyl-piperidyl-Z) ethyl-1'] phenothiazine VII: 3-methyl 10 [2'-(N-methyl-piperidyl-Z") ethyl- 1'] -phenothiazine VIII: 3-hydroxy 1O [2'-(N-methyl-piperidyl-Z)-ethyl- 1'] -phenothiazine IX: 3-bromo 1O [2'-(piperidyl-2)-ethyl-1] phenothiazine It is clear from the foregoing that the adrenolytic activity of Compound I is four times greater than that of Compound VI and three times greater than that of Compound VII. The 3-methoxy-10-[2-(N:methyl-piperidyl- 2")-ethyl-1]-phenothiazine (IV) shows an almost seven times greater activity than Compound VII, and a nine times greater activity than the compound (VI) which is unsubstituted in the 3-position. The isopropoxy-phenothiazine derivative (V) is as much as .28 times stronger than the 3-methyl-phenothiazine-derivative (VII) and 37.5 times stronger than the unsubstituted compound (VI). The narcosispotentiating action of Compounds II, III, IV and V is very good, those of Compounds VI and VII are weak. Compounds VIII and IX lie in the toxic range. Although Compound IX exhibits adrenolytic activity, it is of no practical utility since it lacks the sedative component at non-toxic doses. i

The point of connection to the piperidine ring is also of significance with respect to pharmacodynamic activity. fIhus, the compoundsaccording to the present invention,

6 which have a [2'-(N-methyl-piperidyl-Z")-ethyl-1']- group in the IO-position, are significantly more active than phenothiazines which carry a (N-methyl-piperidyl- 3)-methyl-group in the 10-position of the phenothiazine nucleus. This is shown by the following table.

TABLE IV i CH1 Potentiatlon of hypnosis, EDsc, mg.lkg., Lv.

Adrenolytlc gitencyl,

Compound 00' a manoo It is evident from the foregoing that the adrenolytic activity of the Compounds III and IV is only 7 to 12.5%. Since, in connection with the potentiation of hypnosis activity of these compounds (III and IV) the dose exceeds 10 mg./kg., they must be considered as relatively non-specific.

Comparison, finally, between tertiary and quaternary phenothiazine derivatives shows that quaternization of for example 10 [2' (N methyl piperidyl 2) ethyl- I'J-phenothiazines reduces adrenolytic activity to an extraordinarily great extent, and that the products no longer have a narcosis potentiating action in non-toxic doses. The quaternization of the compound of the formula.

ago

with methyl bromide brings about a very great drop in adrenolytic activity, in that the quaternary compound is 1000 times less active than the tertiary compound. In testing this quaternary compound on the Waking mouse, a striking potentiation of toxicity can be observed. Intravenous doses of 3 mg./kg. have a lethal effect. However, administration of smaller doses does not enhance pentothal-narcosis but, on the contrary, has an exciting action.

The following examples set forth presently preferred representative embodiments of the invention. In these examples, parts (unless otherwise indicated) and percentages are by weight; temperature are in degrees centigrade. The relationship between parts by weight and parts by volume is as that between grams and milliliters. In these examples, as well as in the precednig text, the designation of the substituent positions in the phenothiazine nucleus corresponds to the following:

course ofrtwot hqurs. 1 reaction-mixture is cooled, and excess sodamide' is decomposed by; the addition of 15 parts. of ammonium chloride. The reaction solution is shaken out several times with, in toto', the equal volume of: water, after which v eehl... d m lts at 213-215 if- 32 partsigbt? s-chlbrb-rp en 'ezinei -IP-1.Ch?.IIP.II tier, "a l li t R- l eebl a d' en and --Bu n, c names .rendus, 59', 1952 (melting point= 1'99 .1 1 are dissolved in" the four-fold quantity of absolute xylene,

after which 46.8 parts" as sodarnide (20% excess) are added, and the mixture is heated to boiling under reflux for 2% hours, While stirring. Without interrupting theheating,;a solution of 177.6 parts/of Z-(N-methylquantity of absolute xylene, is added dropwise in the After boiling for: 110 hours, the

thesolutign is evaporated under reduced pressure at '70 .""=Theresultant residue is digested'cold with the tfifC-fbl'd quantitypetroleum"ether'tboiling point: 1 4 the petroleum etherris decanted, from uncon :chloro-phenothiazine, and' the solvent distilled shine..- g

' efi-on-thesteam-bat-hatatmospheric-pressure.----- 7 :The so-obtained residueis distilled under: high vacuum 7 the fraction passing over between 200arid 220 (under a pressure of (1.05. mm. Hg) being collected? ZPurification yields- 3.-.chloro.-1 0- [2 (Nmethyhpigeridyl-Z" -eth-yl- 1 nhenotlsiaa newhieh heils ataz w ;lf 's f I goi mnleflsdiss lved in eme-fold r al d t 9U? iv oehl r 'eajeidt f 25% l t! .g i). added un lft O i h s an. c ea tion 71 'QQ gQ fed," h hidf oehlo idei o ifh 0 ="[2'"-(N? m hy P PI y1- T")'- th "l pheno azine gradlially in ie it n ervs allin iosmt The analy ica ly-pur 278 .17 parts of 3 -I bromo -phenothiazi1ie (melting point=199 -201 are dissolvedin the four-fold quantity 1 of absolute xylene, after which v46.8 parts of sodamide excess) are added, and the mixture is heated .to boiling under reflux for2 /a hours, whilestirring: With; out interrupting the h'eatingQa solutionof' 1 77.6 parts of N 2 (N methyl piperidyl, 2'). 1 chloro ethane (10% excess) in 'an'equal quantity of absolute xyleney is added dropwise in the course of 2 hours. After boiling fo 19! ours thew eaetion mixtu s ee le and. excess 'sp i ii e' ;d Q InP0 d. by. th i i n f 1. par s; i

emm n um. eh' br de- The ea tion. so t o is: a en "0E em f tifile th-tin Mel e. qu ume effee ena 'wh h olu on-i vap r ed und r reduc d pressure :a t 70; The resnltantfresidue is" digested eoljd fv 'fl th ee flqu i petr eum e her (boT 1 O O); t e p role m" ether hi deeanted. f om iihcbnsumed 3 jbromo phenothiazine; and the solvent dis? tilled off on thesteam bath at atmospheric pressure.

: -Tfhe so-obtained residue is' distilled under high vacuu thelfraction' passing over' between .210" and 230 (under 1 "a pressure Qf-0;.05 mm. Hg) being collected. Purifica phenothiazine, the free baseob,tained according to the foregoing example-is dissolved in theten-fold quantity of absolute ethanol, 'and'ethanolic hydrochloric acid (of strength) is added untilgthe'solution has an acid .7 ylrpipenidylez pi-peridyl'-2")z-l-chloro-ethane (10% excess)-1n;an equal kba-sae 1ishamtofisqeawh notniazine as pets lot so;

verizledbsodinmi hydroxidewand .69 p rt by. .VQIHFIQL absolute xtyleneiareahcatedto boiling; for. two; hours, wh le stirring; w azhathztemperatunebfi18D; Without inten- I o 11613561945 zfliiepauitmbyl volmneofi absolute xylene is" added dropwise in the coursehou'nii .iAftee j a heating for three morethoursflnder reflux, the reaction mixture is cooled and"loflfpaitsby lvolume of absolute xylene added. .I he mixtdreis then shaken out, first'threo x times with parts byzvqlume (if water each time-and 7 then once with 120 by voli melof aqueous tartaric 1 acidof 15% strength. The'tar tla'ricacid solution is shaken out twice with, each time, ,30 parts by volume of benzene. i

The aqueous solution is -then'a adjusted to alkalinity to phenolphthalein with; 80 by: volume of aqueous; 'caustic soda solution of 30% strength. The base which, 1

precipitates is shaken outonce with .parts byvolume n t i i hj eeh ti e 2 Pa ts byivv nm ie ben e andtfite beiizen'slutionthn washdtwice with, each 1 im BQpex sv ume f' e e teii h o er a] small-quantity of pot-assiiimear bonate anddistilling on the ben zene, 2 1.$) partsioftcrude oily baserem hind z Upon: di'stiliirigfth been; there is obtained; 3-1od l0-.

e xmmit i e f ire-shrew the. ahyl reemenee rei 9f l pukerizedsodiumeh amxiaejand. me n by j volume of; absolute xylene arei'lia'tedtoiboilingfat a bathtemperg'ture of 189?, undera;refluxfcondenset hav-. e mg a water separator, so; 3 hours while stirring} without; fiZ-a nte rrugtiiig' the heating, a 7 solution of, l4.5 parts 0 litiines, t n} .acid,-' the vaeeti jamd'extra'ct is gwas hedironcewith et h their; rende ed a lotme s phenolphthalein, with so,

part; y i lunie efi easementd aqueous causticf H solutionw'lfhe' reeipitated 'lytib ase is taken up'i'na tota.

V bi qepans olunreofbenzener The benzene layet,

-- w sh l hee we under educed pressu 17.15'1iarth of 3-methoxy-phenothiazinefi(niellti i l' iilf i n't C ,.1 y ro hloride of 3-bromo-10-- t; I y r dx r y 1'1, phend 9 methoxy 10 [2' (N methyl piperidyl 2") ethyl- 1']-phenothiazine has a boiling point of 211 at 0.01 mm. Hg.

EXAMPLE 8 The hydrochloride of the S-methoxy-IO-[2-(N-methylpiperidyl-2")-ethyl-1']-phenothiazine is obtained by rendering the solution of 21.3 parts of the free base in 15 parts by volume of absolute ethanol acid to Congo red by means of ethanolic hydrochloric acid. After the addition of 150 parts by volume of ethyl acetate, the hydrochloride of 3 -methoxy-10-[2'-(N-methyl-piperidyl-Z")- ethyl-l'l-phenothiazine crystallizes out in the cold. It melts at 171-173 (sintering beginning at 165) with evolution of gas.

EXAMPLE 9 Upon the addition to a solution of 12.0 parts of 3- methoxy-10-[2-(N-methyl-piperidyl-2")-ethyl-1']-phenothiazine in 110 parts by volume of ethyl acetate, of a solution of 5.05 parts of tartaric acid in 850 parts by volume of ethyl acetate, the 3-methoxy-10-[2-(N-methyl-piperidyl 2) ethyl-l'l-phenothiazine tartrate crystallizes out. The analytically-pure salt contains one mol of water of crystallization. It decomposes at 115 with foaming, after sintering at about 60.

EXAMPLE 10 3-ethoxy-phenothiazine (melting point=131-132) is prepared by heating N-(m-ethoxy-phenyl)-aniline and sulfur at 160 in the presence of iodine crystals as catalyst.

26.63 parts of 3-ethoxy-phenothiazine, 11.0 parts of finely pulverized sodium hydroxide and 125 parts by volume of absolute xylene are heated to boiling for three hours, at abath temperature of 185, under a reflux condenser fitted with a water separator. Without interrupting the heating, a solution of 19.9 parts of 2-(N- methyl-piperidyl-Z')-1-chloroethane in 45 parts by volume of absolute xylene is added dropwise in the course of two hours. After heating for five more hours, the reaction mixture is cooled and washed three times with water, each time with 75 parts by volume. The xylene solution is extracted once With 50 parts by volume and three times with 25 parts by volume each of 3-normal acetic acid. The acetic acid extract is washed twice with benzene, each time with 30 parts by volume, and is then rendered phenolphthalein-alkaline with 30 parts by volume of concentrated aqueous caustic soda solution. The precipitated oily base is taken up in a total of 175 parts by volume of benzene. The benzene solution, washed with 60 parts by volume of water, is dried over potassium carbonate and, after filtration, is evaporated under reduced pressure; after separating a fore-running fraction distilling up to 212 at 0.01 mm. Hg, the principal fraction3-ethoxy- 10-[2-(N methyl piperidyl 2")-ethyl-1]-phenothiazinedistilling at 212-215 under the said pressure is collected. The analytically-pure base has a boiling point of 213/0.01 mm. Hg.

EXAMPLE 11 Upon addition of a solution of 18.4 parts of 3-ethoxy- 10-[2' (N methyl piperidyl-2")-ethyl-l'l-phenothiazine in 175 parts by volume of ethyl acetate to a solution, cooled to of 7.51 parts of tartaric acid in 1725 parts by volume of ethyl acetate, the tartrate of 3-ethoxy-l0- [2' (N methyl piperidyl-2)-ethyl-11-phenothiazine separates out. The salt, which contains /2 mol of water of crystallization, decomposes above 140, with sintering beginning at 70.

EXAMPLE 12 m-Nitro-isopropoxy-benzene (boiling point-=132-133 10 mm. Hg) is reduced with stannous chloride and hydrochloric acid to m-isopropoxy-aniline (boiling point =126-129/ 10 mm. Hg), which is condensed with potassium o-chlorobenzoate to N-(m-isopropoxy-phenyl)- anthranilic acid (melting point=88-90). The latter is dccarboxylated by heating and distillation under reduced pressure, to yield N-(m-isopropoxy-phenyl)-aniline (boil-v ing point=l94/l0 mm. Hg).

3-isopropoxy-phenothiazine (melting point: 105-107 is prepared by heating N-(m-isopropoxy-phenyl)-aniline with sulfur to 160 in the presence of iodine crystals as catalyst. 20.70 parts of 3-isopropoxy-phenothiazine, 3.76 parts of finely pulverized sodamide and parts by volume of absolute xylene are heated to boiling for two hours with stirring, at a bath temperature of 180, under a reflux condenser. Without interrupting the heating, a solution of 14.65 parts of 2-(N-methyl-piperidyl-Z)-1- chloro-ethane in 15 parts by volume of absolute xylene is added dropwise in the course of two hours. After heating for three more hours, the reaction mixture is cooled and, after the addition of 5 parts of ammonium chloride, is shaken out three times with water, using 25 parts by volume each time. The xylene solution is washed once with 35 parts by volume of 3-normal acetic acid and then three times-each time with 15 parts by volume of 3- normal acetic acid, then the acetic acid extract is washed with 60 parts by volume of benzene and made phenolphthalein-alkaline with 25 parts by volume of concentrated aqueous caustic soda solution. The precipitated oily base is taken up in a total of parts by volume of benzene. The benzene layer, dried over potassium carbonate, is filtered and then evaporated under reduced pressure. The residue from the evaporation is distilled in a high vacuum; after separating a fore-running fraction distilling up to 200 under a pressure of 0.005 mm. Hg, the principal fraction-3-isopropoxy-l0-[2-(N-methyl-piperidyl-Z)-ethyl-1']-phenothiazine-which distills at ZOO-204 under the said pressure is collected. The analytically-pure base boils at 202/0.005 mm. Hg.

EXAMPLE 13 Upon adding a solution of 10.9 parts of 3-isopropoxy- 10-[2'-(N methyl piperidyl 2")-ethyl-1']-phenothiazinc in 100 parts by volume of ethyl acetate to a solution, cooled to 0 C., of 4.27 parts of tartaric acid in 750 parts by volume of ethyl acetate, the tartrate of 3-isopropoxy- 10- [2'-( N-methyl-piperidyl-Z) -ethyl-1] -phenothiazine is precipitated. The salt, which contains /2 mol of water of crystallization, decomposes at with formation of foam after sintering beginning at 80.

EXAMPLE 14 In order to prepare the malate of 3-isopropoxy- 10- [2'-(N-methyl-piperidyl-2")-ethyl-1] phenothiazine, 10.00 parts of the baseobtained as described in Example 12 and 3.51 parts of maleic acid are dissolved in 25 parts by volume of boiling absolute ethanol. To the cooled solution 40 parts by volume of ether are added, the malate precipitating out. The malate of 3-isopropoxy- 10[2'-(N-methyl-piperidyl-2) ethyl-1] phenothiazine crystallizes from absolute ethanol-ether and melts at 105-107.

EXAMPLE 15 N-(m-sec. butoxy phenyl) aniline (boiling point: 0.005 mm. Hg) is prepared by the action of Z-chloro-n-butane on the potassium salt of N-phenylrn-aminophenol (melting point=81.582). By heating the N-(m-sec-butoxy-phenyl)-aniline with sulfur to in the presence of pulverized iodine as catalyst, 3-sec.- butoxy-phenothiazine (melting point=75-77) is obtained. 24.19 parts of 3-sec.-butoxy-phenothiazine, 4.25 parts of finely pulverized sodarnide and 125 parts by volume of absolute xylene are heated to boiling for two hours under a reflux condenser, with stirring and at a bath temperature of 180. Without interrupting the heating, a solution of 16.15 parts of Z-(N-methyl-pipen idyl-2)-1-chloro-ethane in 15 parts by volume of absolute xylene is added dropwise in the course of two hours. After heating for three more hours, the reaction mixture is cooled and, after the addition of 10 parts of ammonium chloride, is shaken out three times with water, using 50 parts by volume each time. The xylene caustic" soda solution.

Phnndthi'azinein 125: parts hydvolume. of; e'thylaee te tgr'alisolutiomi cooled mllfi, of. 6.0 .parts; of; tartaric acid ,im L000; parts. byfvolumez ofi ethylt acetate; their-sccahutoXy-IQ- E21:( N-methyl-piperidylr27 et-hy lllf lrphenothiazincris precipitated. The salt, containing Dyestuffs:

solutiorr'is extracted oncewith" et-meet 3rnormal acetic acid andfihen three times witlr 3tnormdl-' acetic: acidi rising- 2'5" parts hyyolhmeeach" tin mi The acetic acid 'extract is hen washedkwith 100Y15a-rts; voltlrne'ofycther' and" rendered phenolphthaleinalkaline by "means of'35' parts-by volume of concentrated aqueous The precipitated base taken 111i infa. totalof; 200? parts by volume of-benzene? The benzene layrfafter beingclrietl"over potassium care honate', I is filtered" and*' evaporated 'under reduced .iaressnrey after separating a fore-running fraction passing B 'm i #1113209- it under" the said pressure is eeme'cte rz the tantrate or molt oi. water .ot crystalliz tion; r mos e at: L with foaming, after;v sintering; beginning at .It wilh bej'understood. that; inhthe; foregoing: iiamplesi mfierenc made; morejpar'ticularly to the; tartraties;

' recrystallizatl lon'fi'omth five fo'ldgquantity ofpetroleum -hydt;achl'orides= anti; ma1ates,q;because-: -these I are @the 1 tion.' However, theserbases readily iyield 'therapeiiti'callytolerable acid addition saltswi'th [a wide Variety of both organic and, inorganic acids. Thus; by treatihgf the'bases with an equivalent amount of an appropriate acid, as,

for example, hydrobrornic; sulfuric, phosphoric, acetic;

propioni'c, citric, methanesul'fonic "acid, etc'., the corr'e} sporiding hydrobromide, sulfate, *phosphate-,

cet te, propionate; citrate," methanersulfonate; etcg, "wil-hbe formed.

' I The '1'0=['2'-(N alkybpiperidyl-Z') ethyl l'il-f} pheno thiazines and salts thereof obtained according to the foregoing examples can bemadeiup into pharmaceutical preparationsfor, oral or parenteral administ-ratiomin various dosages unit forms. tablets of the following composition can. be made; 7

(:1) "3-isopropo1ry-10-[2'-(N methyl piperidyl-- T 2")-ethyl-1']-phenothiazine 25.00 (2) Gelatine j I50 Nucleus, diameter 7mm., strongly arched 140.00 Coating mass 1 120.00 Sugar-coated tablet $ee the following tabulation: V Mg. White sucrose 85.00 Talcum. 33.5 Gum arabic v 1.5

Tartrazine (Color Indei; rte-.641 o.0.12'

Cochineal Red A (Color Index No. 1's.s.. hoes (Co1or Index; TheaAm. Assoc;v o1:- Textile: Chemists; and QolorletsQiew York,1924).. a Preparationg-The 3' i'sopropoxy -L10'-[2"-(N-niethyl 'pi'peridyl-Z") -ethyl-l]-phenothiazine and approximately 50"percent of the milk sugar are mixed, and 40 percent of the stearic acid,- dissolved in .q.s. ethanol of. 94.0 per i cent strength; is worked together with this mixture. The

whole is granulated with apprbxirnatel-yfi!) percent of the preferred saltsfQf-the;phenothiaz nc ba n li e vfi .For example, sugar-coated therapeutically-tolerable salts thereofswithilaeidi wherein: R is a member selectedLfi-omt ther' g rbnpconl f s iifiesfit l ewed eex;w ih:'-1 1e.4 a which L Thetarrairic-acicland the'remaini'ng' solved in q, s ethanol "of "94; '0j percent strength and .woi ketl together! with Specific grain y;

arelfdissah'etifl while: warrning. i tilled; watersolufion F Thessodinm' chlorie distilledi'waterssolutiontni; I

Solutions-.I'andzm unitedi. aathastolg ssamaau In thefore'going preparations; the 3-isopropoxy-lid-[ lz w 'Haying thusj disclosed"the ihv enndni wh atj 'ijs'claimediiez 1 A componnch'seleetefi from the group consist-iiig oifl 61 6384 moons.-

the declaredi volume and sax-umted witliwcarbondioxide.

sterilized underexcessive pressure at- Im a 1' 13 14 3. A phenothiazine which corresponds to the formula 6. 3 chloro 10 [2'-(N-methyl-piperidyl-Z")-ethy1- S 1]-phenothiazine.

7. 3 bromo 10-[2-(N-methyl-piperidyl-2")-ethyl-1']- phenothiazine.

My 5 8. 3 iodo 10 [2'-(N-methy1-piperidyl-2)-ethy1-1']- I /g];, phenothiazine.

H (IJH' 0H References Cited in the file of this patent E CHI UNITED STATES PATENTS f 2,590,125 Robinson Mar. 15, 1952 cm 2,784,185 Schuler Mar. 5, 1957 wherein the alkoxy group contains 1 to 4 carbon atoms.

4. 3 isopropoxy 10 [2' (N-methy1-piperidy1-2")- ethyl-1'] -phenothiazine.

5. 3 methoxy 10 [2'- (N-methyl-piperidyl-2")- ethyl-1'] -phenothiazine.

OTHER REFERENCES 15 Nieschulz et al.: Arzneimittel Forschung, vol. 4, pp.

232-242 (April 1954).

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 2,902,486 September 1, 1959 Arthur Stoll et al It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, lines 30 to 32, the lower right-hand portion of the formula thould appear as shown below instead of as in the patent e column 6, line 67, for "precednig" read preceding column '7, line 62, for 230" read 230 column 12, lines 58 to 60, the lower right-hand portion of the formula should appear as shown below instead of as in the patent s Signed and sealed this 24th day of May 1960,

(SEAL) Attest: I

KAiliL EL ROBERT C. WATSON utesting Officer Commissioner of Patents 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE PHENOTHIAZINES WHICH CORRESPOND TO THE FORMULA 